CD19-嵌合抗原受体-T细胞免疫治疗对B-ALL患者凝血功能的影响及相关因素研究

Coagulation function changes after CD19-CAR-T cells immunotherapy for B-ALL and its related factors

目的观察CD19-嵌合抗原受体(CAR)-T细胞免疫治疗中,细胞因子释放综合征(CRS)评分不同的急性B淋巴细胞性白血病(B-ALL)患者各类细胞因子和凝血功能的变化。方法对2018年7月至2020年10月在苏州大学附属第一医院接受CD19-CAR-T细胞免疫治疗的87例B-ALL患者治疗前后及30名健康对照者的凝血指标,部分凝血活酶时间(APTT)、凝血酶原时间(PT)、D-二聚体和纤维蛋白原(Fg)进行连续的监测;其中患者的年龄为32(20,56)岁,36例(41.4%)为女性。应用流式细胞术监测B-ALL患者治疗前后体内CD19-CAR-T细胞的比例以及细胞因子白细胞介素-6(IL-6)、细胞因子白细胞介素-10(IL-10)、干扰素-γ(IFN-γ)、肿瘤坏死因子(TNF-α)、IL-2、IL-4和IL-17A表达,并按照共识标准根据严重程度进行CRS分级。结果CRS>3级患者PT、APTT延长,D-二聚体升高,Fg降低(P<0.05)。CRS>3级患者血浆中IFN-γ、IL-6、IL-10细胞因子水平明显高于对照组(P<0.05)。D-二聚体水平与IL-10水平呈正相关。结论CD19-CAR-T细胞免疫治疗中CRS分级严重的患者有的凝血功能紊乱。细胞因子IFN-γ、IL-6和IL-10可能在CD19-CAR-T细胞治疗中影响凝血功能和CRS分级。

Objective To investigate the changes of various cytokines and coagulation function in B cell acute lymphoblastic leukemia(ALL)patients with different CRS scores during CD19-CAR-T cell immunotherapy.Methods 87 patients with B-ALL hospitalized in the First Affiliated Hospital of Soochow University and 30 normal controls were enrolled into this study from July 2018 to October 2020.The age of the patients was 32(20,56)years old and 36(41.4%)were female.All these coagulation indicators,prothrombin time(PT),activated partial thromboplastin time(APTT),D-dimer,fibrinogen(Fg)were analyzed by automatic blood coagulation in B-ALL patients before and after treated with CAR-T cell.The ratio of CD19-CAR-T cells and the expression of IL-6,IL-10,IFN-γ,TFN-α,IL-2,IL-4,and IL-17A were analyzed using flow cytometry.The patients′clinical parameters were detected,and the CRS classification of severity was made according to the standard of consensus.Results Patients with CRS>3 had prolonged PT and APTT,increased D-dimer,and decreased fibrinogen(P<0.05).The levels of cytokines of IFN-γ,IL-6,and IL-10 were significantly higher in patients with CRS>3 than that in controls(P<0.05).The D-dimer level is positively correlated with IL-10.Conclusion Patients with severe CRS grading have significant coagulation dysfunction in CD19-CAR-T cell immunotherapy.Cytokines IFN-γ,IL-6,and IL-10 may affect coagulation function and CRS grading during CD19-CAR-T cell immunotherapy.